title: Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke.
abstract: Cigarette smoke (CS)-induced lung inflammation involves the reduction of histone deacetylase 2 (HDAC2) abundance, which is associated with steroid resistance in patients with chronic obstructive pulmonary disease and in individuals with severe asthma who smoke cigarettes. However, the molecular mechanism of CS-mediated reduction of HDAC2 is not clearly known. We hypothesized that HDAC2 is phosphorylated and subsequently degraded by the proteasome in vitro in macrophages (MonoMac6), human bronchial and primary small airway epithelial cells, and in vivo in mouse lungs in response to chronic CS exposure. Cigarette smoke extract (CSE) exposure in MonoMac6 and in bronchial and airway epithelial cells led to phosphorylation of HDAC2 on serine/threonine residues by a protein kinase CK2-mediated mechanism, decreased HDAC2 activity, and increased ubiquitin-proteasome-dependent HDAC2 degradation. CK2 and proteasome inhibitors reversed CSE-mediated HDAC2 degradation, whereas serine/threonine phosphatase inhibitor, okadaic acid, caused phosphorylation and subsequent ubiquitination of HDAC2. CS-induced HDAC2 phosphorylation was detected in mouse lungs from 2 weeks to 4 months of CS exposure, and mice showed significantly lower lung HDAC2 levels. Thus, CS-mediated down-regulation of HDAC2 in human macrophages and lung epithelial cells in vitro and in mouse lung in vivo involves the induction of serine/threonine phosphorylation and proteasomal degradation, which may have implications for steroid resistance and abnormal inflammation caused by cigarette smoke.
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: David
authors.initials: D
authors.lastname: Adenuga
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Jeanclare
authors.initials: J
authors.lastname: Seagrave
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000201:enzymology; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000378:metabolism*; D013997:Time Factors; D014026:Nicotiana; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D012097:Repressor Proteins; D012906:Smoke; D025801:Ubiquitin; D047390:Casein Kinase II; D046988:Proteasome Endopeptidase Complex; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases